Etiology
Etiology and pathogenesis remain unclear. As the condition is considered to be a severe form of preeclampsia, the causative factors, although still hypothetical, should be similar. Factors that have been discussed include:[10][15]
Abnormal trophoblast implantation followed by defective trophoblast invasion of the spiral arteries and inadequate placental vascular remodeling early in pregnancy
Immunologic intolerance
Inappropriate maternal systemic inflammatory response
Placental release of antiangiogenic factors
Genetic predisposition
Oxidative stress and hypoxia[16]
Peripheral anti-angiogenic imbalance[17]
Altered methylation[18]
Increased proteasome levels/upregulation[19]
Pathophysiology
Characterized by vasospasm and endothelial dysfunction with variable degrees of hepatic ischemic damage, microangiopathic hemolytic anemia, and thrombocytopenia.[22] Vascular changes predominantly affect the liver, and decreased hepatic perfusion may be documented by Doppler exam.[23] The damage may lead to intraparenchymal hemorrhage and/or subcapsular hepatic hematomas, and, rarely, to hepatic infarction.
The liver occupies an important place in the pathogenesis of HELLP syndrome. Variable periportal hepatocyte dysfunction and death/apoptosis causes periportal necrosis that is highly variable among patients and that begins early in the course of disease development.[24] This is probably in relation to the quantity and types of placental-derived and released humoral, inflammatory, and antiangiogenic factors.[25][26] By contrast with acute fatty liver of pregnancy, which is a severe pregnancy complication possibly associated with fetal fatty acid oxidation defects and maternal liver compromise/failure, there is little evidence to suggest that HELLP syndrome is expressed in mothers due to fetal fatty acid oxidation disorders.[15]
The characteristic histologic changes include:[27]
Periportal hemorrhage and necrosis
Focal parenchymal necrosis
Fibrin and hyaline deposits in the hepatic sinusoids
Blood-brain barrier permeability.[28]
The underlying pathophysiology is not completely understood.[15][27][29][30][31] Hypotheses under consideration include:
Immunologic factors (exposure of the maternal immune system to fetal antigens leading to an acute rejection reaction with platelet aggregation, hypertension, and endothelial dysfunction)[27][32]
Placenta-mediated liver injury (the CD-95 ligand, a mediator of hepatocyte apoptosis, has been demonstrated in placental extracts; in vitro, blockage of the ligand reduced the inflammatory damage and the hepatotoxic effect)[29]
The existence of a systemic inflammatory response syndrome (as in any form of severe preeclampsia, the inappropriate release of inflammatory factors causes damage to the endothelium, platelet activation, and vasoconstriction)[30]
The increased inflammatory response of HELLP syndrome is responsive to corticosteroid administration (prednisolone, intravenous dexamethasone); interleukin 6, soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin (sEng) levels decrease significantly in HELLP syndrome patients receiving intravenous dexamethasone in association with improving laboratory parameters of disease[31]
Patients with HELLP syndrome have both an antiangiogenic state and a pronounced inflammatory response, which is in contrast to the dominance of an antiangiogenic shift in patients with preeclampsia.[33] Dexamethasone decreases the release of both antiangiogenic and inflammatory factors.[26]
Classification
Martin/Mississippi classification[2][3][4]
All patients with HELLP syndrome are classified as follows to facilitate management, estimate risk for major maternal morbidity, and compare efficacy of management in published patient series.[4] The classification into 3 classes was introduced into use in 1991 on the basis of severe, moderate, or mild thrombocytopenia and graduated expected severity of maternal illness:[2][3]
Class 1, severe thrombocytopenia: 0 to ≤50,000/mm³, lactate dehydrogenase (LDH) ≥600 IU/L, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥70 IU/L (major maternal morbidity 40% to 60%)
Class 2, moderate thrombocytopenia: >50,000 to ≤100,000/mm³, LDH ≥600 IU/L, and AST and/or ALT ≥70 IU/L (major maternal morbidity 20% to 40%)
Class 3, mild thrombocytopenia: >100,000 to ≤150,000 /mm³, LDH ≥600 IU/L, and AST ≥40 IU/L (major maternal morbidity 20%).
Newest data reveal that patients with severe preeclampsia and patients with class 3 HELLP or incomplete/partial HELLP syndrome have comparable major maternal morbidity of approximately 20%.[5][6]
The Martin/Mississippi classification is a dynamic classification, which changes as the patient deteriorates or improves. Both maternal morbidity and mortality are significantly higher in women whose HELLP syndrome worsens to become class 1 regardless of whether eclampsia is present or not.[7]
Criteria for abnormal levels of liver transaminases and/or LDH to contribute towards a diagnosis of HELLP syndrome are values twice the upper limit of normal concentration not accounted for by alternative diagnoses.[8]
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